Ras genes are frequently activated in human cancers. For example, K-Ras is a member of the small guanosine triphosphate (GTP) binding protein family which constitutes over 100 members. Wild-type K-Ras oscillates between an active, GTP-bound form and an inactive guanosine diphosphate (GDP) form. The GTP-bound form has a distinct conformation that promotes its interaction with multiple effector proteins via its Switch I and Switch II regions. 30% of all solid tumors show activating point mutations in K-Ras. K-Ras mutants are insensitive to down regulation by GAP-mediated hydrolysis of bound GTP. As a result, mutant K-Ras is “frozen” in its activated form which results in constitutive signaling into proliferation and survival pathways. K-Ras point mutations are usually found at codons 12, 13 and 61 and less frequently at codons 59 and 63. Typical point mutations at codon 12 replace a glycine by aspartate or valine. Transgenic mouse models have demonstrated that expression of mutated K-Ras by itself or in combination with the introduction of other oncogenic lesions can promote cancer. Similarly, it was shown that cancer cells undergo apoptosis if oncogenic K-Ras is down regulated by RNA interference. These data strongly suggest that inhibition of oncogenic K-Ras may have therapeutic benefits in cancer patients. K-Ras is farnesylated and located at the inner leaflet of the plasma membrane. In recent years the pharmaceutical industry has attempted to target oncogenic K-Ras proteins by disrupting its subcellular localization with farnesyl transferase inhibitors (FTIs). However, in clinical trials FTIs have proved largely ineffective in pancreatic and other cancers, possibly because the loss of FT activity is compensated for by geranyl-geranyl transferase (Sebti, S. M. & Adjei, A. A. Farnesyltransferase inhibitors, Seminars in Oncology, 31:28-39 (2004)).
There is a need for the development of small molecule therapeutic agents that inhibit Ras.